Crosstalk Between Senescent Bone Cells and the Bone Tissue Microenvironment Influences Bone Fragility During Chronological Age and in Diabetes

Abstract

Bone is a complex organ serving roles in skeletal support and movement, and is a source of blood cells including adaptive and innate immune cells. Structural and functional integrity is maintained through a balance between bone synthesis and bone degradation, dependent in part on mechanical loading but also on signaling and influences of the tissue microenvironment. Bone structure and the extracellular bone milieu change with age, predisposing to osteoporosis and increased fracture risk, and this is exacerbated in patients with diabetes. Such changes can include loss of bone mineral density, deterioration in micro-architecture, as well as decreased bone flexibility, through alteration of proteinaceous bone support structures, and accumulation of senescent cells. Senescence is a state of proliferation arrest accompanied by marked morphological and metabolic changes. It is driven by cellular stress and serves an important acute tumor suppressive mechanism when followed by immune-mediated senescent cell clearance. However, aging and pathological conditions including diabetes are associated with accumulation of senescent cells that generate a pro-inflammatory and tissue-destructive secretome (the SASP). The SASP impinges on the tissue microenvironment with detrimental local and systemic consequences; senescent cells are thought to contribute to the multimorbidity associated with advanced chronological age. Here, we assess factors that promote bone fragility, in the context both of chronological aging and accelerated aging in progeroid syndromes and in diabetes, including senescence-dependent alterations in the bone tissue microenvironment, and glycation changes to the tissue microenvironment that stimulate RAGE signaling, a process that is accelerated in diabetic patients. Finally, we discuss therapeutic interventions targeting RAGE signaling and cell senescence that show promise in improving bone health in older people and those living with diabetes.

Exercise and osteoimmunology in bone remodeling

“…Research has found that bone can not only support the body and protect organs but also can be considered an immune organ 3,4 . At the beginning of the 21st century, the concept of “osteoimmunology” was proposed by Arron, which elaborated on the relationship between the immune system and bone.…”

The multi-faceted nature of age-associated osteoporosis

“…Moreover, age-related bone degradation is accelerated by accumulation of senescent bone cells ( Kassem and Marie, 2011 ). Cellular senescence is a natural process in which cells lose their ability to divide and remain as viable but functionally altered cells, and is triggered by stressors including DNA damage, oncogene activation and inflammatory signals ( Teissier et al, 2022b ). Senescent cells in turn produce inflammatory markers to induce a cycle of bone remodeling, and can induce senescence in neighbouring cells.…”

Amorphous calcium phosphate-coated surfaces as a model for bone microenvironment in prostate cancer

“…Importantly, this bone microenvironment is the primary repository of calcium, which is incorporated and mobilized from the osteoid matrix to respond to systemic demand (reviewed in Murshed, 2018; Tresguerres et al, 2020). Factors like race (Noel et al, 2021), age (I.O.F., 2022; Veldurthy et al, 2016), and concomitant morbidities like diabetes (Ahn et al, 2017; Cipriani et al, 2020; Jackson and Moseley, 2020; Teissier et al, 2022) impact bone calcium homeostasis: they can result in osteopenia (loss of calcified bone mineral density) and osteoporosis (loss of mineral density that results in decreased bone strength). Adding complexity to these phenotypes, the standard of care for prostate cancer also negatively impacts bone matrix integrity.…”